(N)-Methanocarba ([3.1.0]bicyclohexyl) adenosines and corresponding ribosides were synthesized to identify novel A1 adenosine receptor (A1AR) agonists for CNS or peripheral applications. Human and mouse AR binding was determined to assess the A1AR compatibility of the constrained ring system in adenosine analogues in combination with N6, C2 and C5’ substitution. An N6-dicycloalkyl ribose agonist (MRS7469) was &gt;2000-fold selective for A1AR in two species and drug-like, based on in vitro and in vivo ADME-tox testing. The pure N6-(S)-endo-norbornyl diastereoisomer of known riboside Cl-ENBA displayed high hA1AR selectivity. Methanocarba modification reduced A1AR selectivity of N6-dicycloalkylmethyl and endo-norbornyl adenosines, but when applied to the antiviral drug ribavirin increased A1AR selectivity compared to the riboside. Thus, alternative nucleobases can be considered in the design of A1AR agonists. Most analogues tested (ip.) were inactive or weak in inducing mouse hypothermia, despite mA1AR full agonism and variable mA3AR efficacy, but strong hypothermia by MRS7469 depended on A1AR with peripheral A3AR participating (determined using A1AR or A3AR null mice). The interaction of the nucleosides with the hA1AR was modeled using the recently determined cryo-EM structure of an active state hA1AR. Conserved H-bonds were preserved in modeling of MRS7469 and methanocarba equivalent MRS7587. Thus, we identified, and characterized in vivo and computationally, novel ribose and methanocarba-modified nucleosides that potently activate A1AR.

Comparison of native ribose and conformationally-constrained (N)-methanocarba nucleosides for A1 adenosine receptor agonists: Design and in vivo characterization

2019 Spring National Meeting

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